The present invention relates to a dosage form for administering a physiologically active substance (A), wherein the dosage form is mechanically stabilised, such that it cannot be comminuted by conventional methods, such as pounding, crushing, grinding in a mortar etc., or at least comminuted only with very great difficulty. The substance (A) is released from the dosage form according to the invention under physiological conditions with an at least partially delayed release profile.
Numerous physiologically active substances, such as nutritional supplements, pharmaceutical substances etc., are provided as delayed-release formulations, i.e., in contrast to conventional formulations (for example “immediate release” formulations), release of the substances from these formulations into the body is delayed for a comparatively long period, which often amounts to several hours. Release of the substance from the dosage form, on the one hand, and metabolisation or excretion by the organism; on the other hand, ensure a relatively uniform blood plasma level for the administered substance. As a consequence thereof, the number of dosage units which need to be taken per day by patients can frequently be reduced, intake often being required only once or twice a day.
In certain cases, delayed-release formulations may also reduce the extent of side-effects caused by the substance. Thus, for example, some pharmaceutical substances produce intensified side-effects if a given limit concentration of the pharmaceutical substance in the blood plasma is exceeded at least transiently. Such pharmaceutical substances are therefore generally unsuitable for “immediate release” formulations, in particular if it is desired to administer said formulations only two or three times daily. Such pharmaceutical substances are therefore conventionally administered as delayed-release formulations, whereby continuous release of the active ingredient is ensured and short-term occurrence of elevated concentrations is prevented.
In delayed-release formulations, the physiologically active substance is conventionally either embedded in a matrix controlling release and/or the dosage form is coated with a film which controls release.
However, older patients in particular frequently have difficulties in taking solid dosage forms, such as tablets, gelatine capsules, etc. They choke on them and sometimes develop pronounced aversion to such dosage forms.
To counter this problem, various apparatuses have been developed by means of which solid dosage forms may be comminuted or pulverised (“tablet crushers”). Such apparatuses are used, for example, by the care staff in old people's homes. The dosage forms are then administered to the people being cared for not as tablets etc. but rather as powder, for example to get round the difficulties involved in swallowing tablets.
However, the comminution of dosage forms with such apparatuses is problematic if the dosage forms are delayed-release formulations. As a rule, comminution then results in destruction of the inner structure of the dosage form, which is responsible for the delayed release, so doing away with the delayed-release action. As a result of comminution, the diffusion paths of the physiologically active substances contained therein are shortened and/or the diffusion barriers are removed. For instance, a delayed-release formulation in which delayed release is achieved by means of a film coating exhibits the film coating over only a small percentage of its solid surface after comminution. Consequently, after administration, frequently all the physiologically active substance originally contained in the dosage form is released in a relatively short time, whereby a comparatively very high plasma concentration of the substance is abruptly reached for a relatively short period. In this way, the original delayed-release formulations become “immediate release” formulations.
Depending on the physiological activity of the substance, this may cause considerable side-effects however, and in extreme cases may even lead to the death of the patient. Examples of substances with such a hazard potential are antiparkinson drugs, antiepileptics, antidiabetics, antihypertensives, antiarrhythmics, etc.
As a rule, the people who comminute the dosage forms for themselves or for others are not aware of these risks. Cases are known in which patients have died probably as a result of pulverisation of delayed-release formulations by nurses or carers. For further details, reference may be made for example to J. E. Mitchell, Oral Dosage Forms That Should Not Be Crushed: 2000 Update, Hospital Pharmacy, 2000; H. Miller et al., To Crush or Not to Crush, Nursing 2000; R. Griffith et al., Tablet Crushing and the law: the implications for nursing; Prof. Nurse 2003; J. G. Schier et al, Fatality from administration of labetalol and crushed extended-release nifedipine, Ann. Pharmacotherapy 2003; A. James, The legal and clinical implications of crushing tablet medication, Nurse Times 2005, 100(50), 28-9; and P. Cornish, “Avoid the Crush”: hazards of medication administration in patients with dysphagia or a feeding tube, CMAJ. 2005, 172(7), 871-2.
Delayed-release formulations may also cause problems for small children. For instance, children frequently cannot distinguish solid dosage forms from sweets. If children find such dosage forms, for example because their parents have carelessly left them lying around in the home, there is a risk that the children may think that the dosage forms are sweets and put them in their mouths and chew them. If said dosage forms are delayed-release formulations, which contain a pharmaceutical substance in a dosage intended for adults, the child may in such a case already be at risk of overdose due to the relatively large amount of pharmaceutical substance contained therein. By chewing the dosage form and thus cancelling out the delayed-release action, this risk is increased still further, however, since the excessively high dose already contained therein is additionally released over a greatly reduced period of time, a situation which would be very hazardous even for an adult and which may have all the more drastic consequences for a child.
The chewing of delayed-release formulations may also lead to an overdose of the substance contained therein in adults. Sometimes adults chew the dosage forms deliberately, though often in ignorance of the type and purpose of a delayed-release formulation, because they hope for a quicker effect.
A known way of reducing the risks involved in comminuting delayed-release formulations consists in adding to the dosage form antagonists, i.e. antidotes, or compounds which produce defensive reactions, wherein the physiological action of these additives are as far as possible manifested only if the dosage form has been comminuted prior to administration. This method has the disadvantage, however, that the physiologically active substance is nonetheless administered in non-delayed form and that the organism is additionally exposed to a further physiologically active substance, for example an antidote, or to a defensive reaction, such as for example vomiting.
There is a need for pharmaceutical dosage forms with delayed release which reduce the risk of overdose, such that e.g. antidotes etc. may be dispensed with.
Thus, it is an object of the invention to provide a dosage form having advantages over the dosage forms of the prior art. The dosage form should release a physiologically active substance on a delayed-release basis but should reduce the risk of overdose, in particular as a consequence of improper handling of the dosage form, such as chewing, crushing, grinding in a mortar etc.